Leishmaniasis encompasses a complex of diseases with diverse clinical outcomes that include localized or widespread cutaneous, mucosal and visceral syndromes. The majority of people infected with Leishmania control infection and remains asymptomatic. However, the mechanisms that medicate control infection and whether there is parasite clearance are not known. American tegumentary leishmaniasis (ATL) due to L. braziliensis evolves with a biased immune response to parasite antigens manifested by high TNFa and INFy but low IL-10. In contrast, visceral leishmaniasis (VL) presents with high levels of IL-10 and TNFa and low levels of INFy. In recent studies we have shown that IL6 and loci controlling the wound healing response are associated with tegumentary leishmaniasis, and that HLA is associated with the outcome of L. i. chagasi infection. We hypothesize that the clinical spectrum of Leishmania infections is determined by immune responses regulated locally at the site of infection and reflected in the periphery, providing potential biomarkers for disease progression or recovery. Major emphases of this proposal will be address the contrasts between the outcomes of infection with different species of Leishmania and the human host responses. We propose to study novel pathways of gene expression that are influenced by major genetic risk factors, allowing us to progress to the identification of signatures that will predict disease outcome that can be applied clinically in the management or prevention of disease. The major goals of this study are: (1) To determine the downstream pathways regulated by host genes shown to influence VL and ATL through transcriptional profiling of infected tissues and peripheral blood; (2) To understand the functional correlates and epigenetic regulation of IL6 and FLU in ATL; and (3) To identify the immunologic mechanisms determining the different phenotypes in L. i. chagasi-infection and to define whether variability in host immune response to Leishmania antigens is due to HLA. These studies will provide infonmation about novel targets for therapeutic intervention by delineating the mechanisms that lead to parasite control and clearance and by identifying molecular signatures in the blood or infected tissues that can be targeted.